Millions of people around the world regularly consume arsenic-contaminated water. Arsenic exposure has previously been linked to the development of various types of cancer, including skin cancer. Studies on the molecular mechanisms regulating arsenic-induced carcinogenesis are still scarce. Using in vitro studies, researchers in Japan are showing how calcitriol, or activated vitamin D3, inhibits arsenic-induced carcinogenesis in certain types of skin cells called "keratinocytes."
According to recent estimates, more than 140 million people in 50 countries are regularly exposed to arsenic through drinking contaminated water. The level of exposure is well above the guideline value (10 μg/L) set by the World Health Organization. Chronic exposure to arsenic from drinking water is recognized to cause various types of cancer, including skin cancer. Unfortunately, general data on the biological mechanisms regulating arsenic-induced carcinogenesis are lacking. In addition, methods to prevent and treat arsenic-induced carcinogenesis remain elusive.
Researchers at the Shibaura Institute of Technology (SIT) and Nagoya University have recently been able to identify the underlying biological mechanisms of carcinogenesis inhibition. Using in vitro studies, the research team was able to show how calcitriol, or activated vitamin D3, inhibits arsenic-induced carcinogenesis in certain types of skin cells called 'keratinocytes'. These cells are mainly present in the epidermis, which is the outermost layer of the skin. It has been scientifically established that certain signaling molecules - kinase proteins (eg MEK or 'AKT') that control the course of various biological processes - are strongly associated with the development of tumors.
Professor Ichiro Yajima of the Unit of Molecular and Cellular Toxicology, Department of Bioscience and Engineering at SIT, who led the research team, says: "Our in vitro studies on nontumorigenic HaCaT skin keratinocytes in humans showed that calcitriol, also known as activated vitamin D3 or 1, 25-dihydroxyvitamin D3 inhibits arsenic-induced growth without substrate retention while reducing cancer-associated activation of a number of signaling pathways, including the MEK, ERK1/2 and AKT pathways, as well as cell cycle activity."
To elucidate the relationship between arsenic uptake and calcitriol treatment, researchers measured arsenic levels in HaCaT cells - persistent, spontaneously immortalized human epidermal keratinocytes - treated with calcitriol using an inductively coupled plasma mass spectrometer. Interestingly, arsenic levels in HaCaT cells cultured with arsenic decreased significantly when these cells were treated with increasing doses of calcitriol. The results of this research have been published in the American Journal of Cancer Research.
Dr. Masashi Kato, who serves as a professor in the Department of Occupational and Environmental Health at Nagoya University in Japan and is a collaborator on the study, adds: "Calcitriol significantly reduced arsenic uptake in HaCaT cells by regulating the expression of aquaporin genes (AQP7, 9 and 10), which were modified by exposure to arsenic. The expression of the vitamin D receptor was significantly increased by exposure to arsenic, while the expression of the receptor was not affected by calcitriol."
The researchers then set out to investigate whether calcitriol had an inhibitory effect on arsenic-induced carcinogenesis in cells other than dermal keratinocytes. To this end, medium-independent growth assays were performed using a human normal lung epithelial cell line named "Beas-2b". The results of these assays were equally astonishing: substrate-independent growth in calcitriol-treated Beas-2b cells was suppressed ranging from 21.4% to 70.0%, suggesting that the potential of calcitriol to inhibit arsenic-induced carcinogenesis is not limited to keratinocytes .
